The present invention relates to a method of producing 2,4xe2x80x2-dipyridyl derivatives, a method of separating 2,4xe2x80x2-dipyridyl derivatives, and methods of producing benzoxazepine derivatives and their salts. More specifically, it relates to a method of producing 2,4xe2x80x2-dipyridyl derivatives by a cross coupling reaction of halopyridines, a method of separating a 2,4xe2x80x2-dipyridyl derivative from a dipyridyl derivative isomer mixture containing the 2,4xe2x80x2-dipyridyl derivative, and methods of producing benzoxazepine derivatives and their salts using the above methods.
Various reports have been made up to now on methods for synthesis of 2,4xe2x80x2-dipyridyl, but all of these methods of synthesis involve problems. None of the methods of synthesis are satisfactory.
For example, in the condensation reaction of 4-cyanopyridine and acetylene disclosed in the specification of U.S. Pat. No. 4,196,287, there is the danger of explosion since a high pressure acetylene gas is used, and therefore, special equipment is required, and the method is not generally accepted.
Further, in the Ullmann-like reaction of 2-halopyridine and 4-halopyridine (Khim. Geol. Nauk., vol. 5, p. 114, 1970), 2,2xe2x80x2-dipyridyl and 4,41-dipyridyl are produced, in addition to the desired 2,4xe2x80x2-dipyridyl, and therefore, the yield is poor.
Further, cross coupling reactions between a halopyridine and various pyridine metal reagents (see Grignard reagent: Synthesis, vol. 7, p. 564, 1986; tin reagents: T. L., vol. 33, no. 16, p. 2199, 1992; borane reagent: Chem. Pharm. Bull., vol. 33, no. 11, p. 4755, 1985) using a palladium catalyst has been reported in numerous conditions, but isomers such as 2,2xe2x80x2-dipyridyl and 4,4xe2x80x2-dipyridyl are produced in large amounts in addition to the desired 2,4xe2x80x2-dipyridyl, and therefore, the yield is poor and the purification is very tedious.
Further, as another method, the reaction with an N-ethoxycarbonyl pyridinium salt (see J. Chin. Chem. Soc. (Taipei), vol. 36, no. 6, p. 609, 1989) was reported, but the yield is extremely poor and in the improved method (see Heterocycle, vol. 31, no. 4, p. 637, 1990), the number of reaction steps is tremendously increased, and therefore, this method is not practical.
There have been other methods reported in literature, but the synthetic routes are long and the yields of all of the processes are low (for example, see T.L., vol. 25, no. 35, p. 3887, 1994 and Pol. J. Chem., vol. 53, no. 4, p. 893, 1979).
As explained above, all of the reported methods of 2,4xe2x80x2-dipyridyl up to now have been poor in yield or have not been easy in operation and were not industrially satisfactory. Further, the simple removal method of the isomers, i.e., 2,2xe2x80x2-dipyridyl or 4,4xe2x80x2-dipyridyl, which were sometimes produced has not been studied at all.
The object of the present invention is to provide a method of producing 2,4xe2x80x2-dipyridyl derivatives which is good in yield, easy in operation, and industrially satisfactory and a simple method for separating the 2,4xe2x80x2-dipyridyl derivatives from a mixture of dipyridyl derivative isomers.
Another object of the present invention is to provide an industrially satisfactory method of producing benzoxazepine derivatives and the salts thereof, using the above method.
The present inventors engaged in intensive studies in consideration of the above situation with the intent of establishing a method for the industrial production of 2,4xe2x80x2-dipyridyl derivatives and easy separation and refinement of its isomers as a result found that with a coupling reaction between a 2-halopyridine derivative of the formula (I): 
wherein X represents a halogen atom and R3 and R4 independently represents a hydrogen atom, a halogen atom, or a C1-C4 lower alkyl group and 4-halopyridine is carried out using a nickel complex catalyst, a 2,4xe2x80x2-dipyridyl derivative is simply obtained with a good yield and, further due to the difference in chelating abilities among dipyridyl isomers, the process of separation and purification of the desired 2,4xe2x80x2-dipyridyl derivative from the byproduct 2,2xe2x80x2-dipyridyl derivative and 4,4xe2x80x2-dipyridyl, can be effected by using copper sulfate to insolubilize the by-products as copper salts, whereby the present invention has been completed.
In the present invention, in the above general formula (I), when X is C1, R3 and R4 are preferably F as halogen atoms and are preferably methyl groups and ethyl groups as the lower alkyl groups. In the most preferable combination of R3 and R4, R3 and R4 are the same and are hydrogen atoms. According to the present invention, by using a 2-halopyridine derivative and 4-halopyridine as the starting materials, using the nickel complex catalyst used for homoaryl coupling (J. Organomet., Chem., 1971, vol. 28, p. 287), and performing a coupling reaction in the presence of zinc and a tetraalkylammonium halide salt, a 2,4xe2x80x2-dipyridyl derivative can be obtained with a good yield in a single step.
Further, depending on the reaction conditions, in addition to the 2,4xe2x80x2-dipyridyl derivative, small amounts of 2,2xe2x80x2-dipyridyl derivative or 4,4xe2x80x2-dipyridyl may be produced as by-products. The separation of only the 2,4xe2x80x2-dipyridyl derivative from the mixture of these dipyridyl isomers can be achieved as follows. Due to the difference in the chelating ability among dipyridyl isomers, it has been found that, by dissolving the mixture of the dipyridyl derivative isomers in an organic solvent, followed by adding a dilute copper sulfate solution, then stirring, the 2,2xe2x80x2-dipyridyl derivative and 4,4xe2x80x2-dipyridyl formed copper salts and precipitated as insolubles. By filtering out these insolubles using Celite etc., it is possible to obtain just the desired 2,4xe2x80x2-dipyridyl derivative in the organic solvent layer. By condensing this organic layer under reduced pressure, only the pure 2,4xe2x80x2-dipyridyl derivative can be obtained.
Further, according to this method, benzoxazepine derivatives and its salts can be industrially advantageously obtained.
The 2-halopyridine derivative capable of being used in the method of production of a 2,4xe2x80x2-dipyridyl derivative by a coupling reaction of the present invention is a 2-bromopyridine derivative or a 2-chloropyridine derivative. The 4-halopyridine is 4-bromopyridine or 4-chloropyridine. These may be added to the reaction mixture as free amines or pyridinium salts, or added after being neutralized by an amine in an organic solvent.
The molar ratio of the 2-halopyridine derivative and the 4-halopyridine is preferably 4:1 to 1:4, more preferably 1:1. Even if the amount of 2-halopyridine is present in excess, the 2,4xe2x80x2-dipyridyl derivative is preferentially produced (see Examples 1 and 2).
The nickel complex catalyst used in the coupling reaction is, for example, bis(triphenylphosphine) nickel (II) dihalides, such as NiCl2 (PPh3)2, NiBr2 (PPh3)2, NiI2 (PPh3)2, NiCl2 [Ph2P(CH2)2 PPh2], NiCl2 [Ph2P(CH2)3PPh2], or Ni (PPh3)4, Ni(1,5-cyclooctadiene)2 (Ph indicates phenyl group), preferably NiCl2 (PPh3)2, NiBr2 (PPh3)2, NiCl2 [Ph2P(CH2)2PPh2], or Ni (PPh3)4, most preferably NiCl2 (PPh3)2 or NiBr2 (PPh3)2 is used in an amount of preferably 10 to 50 mol %, more preferably 30 mol %, based upon the 2-halopyridine derivative and 4-halopyridine.
When the catalyst is bivalent nickel, the reaction proceeds well in the copresence of zinc.
The zinc used in the reaction is used in an amount-of preferably 1 to 4 equivalents, more preferably 1.5 equivalents, of the 2-halopyridine derivative and 4-halopyridine. The alkyl group constituting the tetraalkylammonium halide, is preferably a lower alkyl group, more preferably a methyl group, ethyl group, n-propyl group, or n-butyl group, most preferably an ethyl group or n-butyl group. The halogen is iodine or bromine and is used in an amount of preferably 0.1 to 3 equivalents, more preferably 1 equivalent, of the 2-halopyridine derivative and 4-halopyridine.
When performing the coupling reaction of the 2-halopyridine derivative and 4-halopyridine, a nickel complex, zinc, and tetraalkylammonium halide are reacted in an organic solvent, for example, tetrahydrofuran, toluene, acetone, ethyl ether, dimethyl formamide, or their mixtures, preferably tetrahydrofuran, to obtain a catalyst solution, and then to this solution, the 2-halopyridine derivative or a salt thereof and 4-halopyridine or a salt thereof are added directly or as a mixture prepared in advance. The mixture thus obtained is comprised of the 2-halopyridine derivative or a salt thereof and 4-halopyridine or a salt thereof neutralized in an organic solvent. As the organic solvent, for example, acetone, tetrahydrofuran, ethyl ether, or dimethylformamide, preferably dimethylformamide, is used. The amine is preferably triethylamine.
The reaction of the 2-halopyridine derivative and 4-halopyridine is performed preferably at 0xc2x0 C. to 70xc2x0 C., more preferably 40xc2x0 C. to 60xc2x0 C., but if the temperature rises too high at the time of addition, the yield is decreased, and therefore the solution is appropriately cooled through the addition.
When using dimethylformamide as the reaction solution, the reaction is also carried out without using a tetraalkylammonium halide (see Examples 5 and 8).
Further, the concentration of the reaction mixture is preferably medium to low concentration since the presence of the catalyst as a solid in the reaction mixture makes its reaction at a high concentration difficult (see Examples 17 and 18).
The reaction mixture is poured into a dilute aqueous ammonia solution to terminate the reaction then an organic solvent is added, the insolubles are filtered out, and a separation operation performed to obtain an organic layer which is then condensed. In the reduced pressure distillation of the organic layer, separation from phosphine or other isomers is difficult. In the present invention, the following two separation methods may be used.
1. By Column Chromatography (see Examples 1 to 9)
The above condensate is dissolved in an organic solvent and subjected to silica gel column chromatography, whereupon triphenylphosphine is eluted by hexane, 2,2xe2x80x2-dipyridyl derivative is eluted by hexane-ethyl acetate (4:1), the desired 2,4xe2x80x2-dipyridyl derivative is eluted by ethyl acetate, and 4,4xe2x80x2-dipyridyl is eluted after the 2,4xe2x80x2-dipyridyl derivative.
2. By Formation of Copper Salt (Examples 10 to 18)
When separating and purifying the 2,4xe2x80x2-dipyridyl derivative from the reaction mixture, the separation of the triphenylphosphine and dipyridyl derivative mixture is performed by transfer to an aqueous layer in the presence of an acid, preferably hydrochloric acid (gas or aqueous solution), then the aqueous layer is made basic and extracted with an organic solvent. The 2,4xe2x80x2-dipyridyl derivative is separated from the mixture of dipyridyl isomers contained in the extract by insolubilizing the 2,2xe2x80x2-dipyridyl derivative and 4,4xe2x80x2-dipyridyl by a dilute aqueous copper sulfate solution.
To make the copper salts formed other than that of the 2,4xe2x80x2-dipyridyl derivative selectively precipitate, the setting of the concentration of the copper sulfate is important. A range of 0.1M to 0.2M is desirable.
As the extraction solvent, any organic solvent can be used if it can be separated from water and is low in toxicity, but in general toluene, ethyl acetate, chloroform, tetrahydrofuran, or ethyl ether is preferred.
As mentioned above, a method of separation of a 2,4xe2x80x2-dipyridyl derivative from a reaction mixture by a cross coupling reaction using a 2-halopyridine derivative and 4-halopyridine as the starting materials and using a nickel complex catalyst is described, but the method of separation of the 2,4xe2x80x2-dipyridyl derivative of the present invention clearly can also be used for the separation of a 2,4xe2x80x2-dipyridyl derivative from a mixture of 2,21-dipyridyl derivative, 2,4xe2x80x2-dipyridyl derivative, and 4,4xe2x80x2-dipyridyl synthesized by any other method.
The present inventors conducted intensive studies on synthesis using affinity with a serotonergic receptor and the affinity with a dopamine D2 receptor as activity indicators and found that the specific benzoxazepine derivatives and their salts having the formula (III) exhibit an anxiolytic activity confirmed by the anticonflict activity and that they have suppressive activity in cerebral infarction and other protective effect of the brain in ischemic brain diseases in a transient right middle cerebral artery occlusion (MCAO) model, and therefore, found that these compounds were useful as more effective pharmaceuticals with less side effects used for the treatment of anxiety neurosis, phobias, obsessive-compulsive disorders, schizophrenia, post-cardiac trauma stress disorders, depression disorders, psychosomatic disorders and other psychoneurotic disorders, eating disorders, menopausal disorders, infantile autism and other disorders, and also emesis or disorders involving the cerebral circulatory system accompanying cerebral infarction and cerebral hemorrhage (see specification of International Patent Publication WO/96/24594). They then found a useful method for the production of the same and completed the present invention.
Accordingly, another object of the present invention is to provide method of production of said benzoxazepine derivatives.
In accordance with the present invention, there is further provided a method of producing benzoxazepine derivatives having the formula (III): 
wherein n represents an integer of 2 to 5, R1 represents a hydrogen atom, a halogen atom, C1-C4 lower alkyl group, C1-C4 lower alkoxyalkyl group, C1-C4 halogenoalkyl group, cyano group, or ester group, R2 represents a hydrogen atom, a halogen atom, C1-C4 lower alkyl group, C1-C4 lower alkoxy group, or hydroxy group, R3 and R4 independently represent a hydrogen atom, halogen atom, or C1-C4 lower alkyl group, and a dotted line indicates the presence or absence of a bond and its salts.
In accordance with the present invention, there is further provided a method of producing benzoxazepine derivatives having the formula (V): 
wherein n, R1, and R2 are as defined above and Q indicates a hydroxy group, alkoxy group, halogen, or leaving group capable of being easily exchanged with an amino group and its salts. This is useful as a method of production of an intermediate for synthesis of the benzoxazepine derivatives having the formula (III) and salts thereof.
In accordance with the present invention, further, there is provided a method of production of a benzoxazepine derivative having the formula (VI): 
wherein, n, R1, R2, R3, and R4 are as defined above and X represents a halogen atom and its salts. This is useful as a method of production of a synthetic intermediate of the benzoxazepine derivative having the formula (III) and its salts.
Furthermore, a more detailed explanation will now be given of the mode of working the invention in the method of production of the compound having the formula (III) according to the examples of the present invention, but of course the present invention is not limited to these examples.
In the compound of the formula (III), as preferable examples of the integer n in the formula, 3 to 5 may, be mentioned, in particular, 4 is preferable. As preferable examples of the group R1 in the formula (III), a hydrogen atom, C1-C3 lower alkyl group, C1-C3 lower alkoxyalkyl group, C1-C2 halogenoalkyl group, chlorine atom, or nitrile group may be mentioned, but a hydrogen atom, methyl group, ethyl group, methoxymethyl group, chloromethyl group, or chlorine atom is particularly preferable. As preferable examples of the group R2, a hydrogen atom, halogen atom, C1-C2 lower alkyl group, C1-C2 lower alkoxy group, or hydroxy group may be mentioned, but a hydrogen atom, fluorine atom, chlorine atom, methyl group, or methoxy group is particularly preferable.
The method of production of a compound having the formula (III) according to the present invention is, for example, the following method of production:
First, in the intermediate compound having the formula (V) according to the present invention, the preferable examples of the integer n in the formula are 3 to 5, more preferably 4. The preferable examples of the group R1 in the formula are, a hydrogen atom, C1-C3 lower alkyl group, C1-C3 alkoxyalkyl group, C1-C2 halogenalkyl group, chlorine atom, and nitrile group, particularly preferably a hydrogen atom, methyl group, ethyl group, methoxymethyl group, chloromethyl group, or chlorine atom. The preferable examples of the group R2 are, a hydrogen atom, halogen group, C1-C2 lower alkyl group, C1-C2 lower alkoxy group, and hydroxy group, particularly preferably a hydrogen atom, fluorine atom, chlorine atom, methyl group, or methoxy group. Further, the preferable examples of the leaving group easily exchangeable with a hydroxy group, alkoxy group, halogen, or amino group of the group Q in the formula are a tosyl group, mesyl group, chlorine atom, bromine atom, and iodine atom, particularly preferably a chlorine atom, bromine atom, or iodine atom.
The production method of a useful synthetic intermediate having the formula (V) may be, for example, comprised as follows. The production method of the compound having the formula (V) where, for example, R1 and R2 are hydrogen atoms and Q is a chlorine atom, that is, a compound having the formula (Va): 
wherein n is the same as defined above, is comprised of reacting the compound, obtained according to the method described in the reference of H. Hofmann et al. (Liebigs Ann. Chem., p. 917, 1990) or similar methods, having the formula (X): 
with, for example, bromochloroalkane, to obtain the useful synthetic intermediate, benzoxazepine derivative (Va).
Also in the production method of a compound having the formula (V), a production method of the compound having the formula (V) where, for example, R1 is a methyl group, R2 is a hydrogen atom, and Q is a chlorine atom, i.e., a compound having the formula (Vb): 
wherein n is the same as defined above, is comprised of reacting the compound, obtained according to the method described in the reference of J. Freedmann et al. (J. Heterocyclic Chem., vol. 27, p. 343, 1990) or similar methods; having the formula (XI): 
with, for example, bromochloroalkane, to obtain the useful synthetic intermediate, benzoxazepine derivative (Vb).
Furthermore, in the production method of a compound having the formula (V), a production method of the compound (V) where, for example, R1 is a halogen atom such as a chlorine atom, R2 is a hydrogen atom, and Q is a chlorine atom, a compound having the formula (Vc): 
wherein n is the same as defined above, is comprised of reacting the compound, obtained according to the method described in the reference of A. Cattaneo et al. (Boll. Chim. Farm., vol. 102, p. 541, 1963) or similar methods, having the formula (XII): 
with, for example, bromochloroalkane to obtain a compound having the formula (XIII): 
wherein n is the same as defined above, then, reacting with an acid chloride such as phosphorus oxychloride, thionyl chloride, while optionally adding an acid such as hydrochloric acid or a base such as N,N-diethylaniline, to obtain the useful synthetic intermediate, benzoxazepine derivative (Vc).
The production method of the benzoxazepine derivative (Vc) may further be comprised of the following separate method, as an alternative method. That is, the compound having the above general formula (XII) is reacted with an acid chloride such as phosphorus oxychloride, thionyl chloride, while optionally adding an acid such as hydrochloric acid or a base such as N,N-diethylaniline to convert the same to a compound having the formula (XIV): 
and reacting with, for example, bromochloroalkane.
In the production method of a compound having the formula (V), a production method of the compound (V) where, for example, where R1 is a halomethyl group, for example, a chloromethyl group, R2 is a hydrogen atom, and Q is a chlorine atom, a compound having the formula (Vd): 
wherein n is the same-as defined above, is comprised of reacting the compound of the above, intermediate (Vb) with N-chlorosuccinimide, to obtain the useful synthetic intermediate, benzoxazepine derivative (Vd).
Further, in the production method of a compound having the formula (V), a production method of the compound (V) where, for example, where R1 is a C1-C4 lower alkoxymethyl group, for example, a methoxymethyl group, R2 is a hydrogen atom, and Q is a bromine atom, a compound having the formula (Ve): 
wherein n is the same as defined above, is comprised of reacting the compound of the above intermediate (XI) with N-chlorosuccinimide to convert the same to the compound (XV) having the following structure: 
then using sodium methoxide to convert the same to a compound having the following structure (XVI): 
followed by reacting with dibromoalkane, to obtain the useful synthetic intermediate, benzoxazepine derivative (Ve).
In the production method of a compound having the formula (V), a production method of, for example, a compound having the formula (Vf): 
where n is the same as defined above, i.e., R1 is a hydrogen atom, R2 is an alkoxy group, for example, 7-methoxy group, and Q is a chlorine atom in the formula (V), is comprised of following the method described in the above reference of H. Hofmann et al. or similar methods to obtain the compound having the formula (XVII): 
then following the same procedure for synthesizing a compound having-the above formula (Va).
In the production method of a compound having the formula (V), a production method of, for example, a compound having the formula (Vg): 
wherein n is the same as defined above, i.e., R1 is an alkyl group, for example, a methyl group, R2 is an 8-hydroxy group, and Q is a chlorine atom in the formula (V), is comprised of following the method described in the above reference of J. Freedmann et al. or similar methods to obtain the compound having the formula (XVIII): 
then following the same procedure as synthesizing the compound having the above formula (Vb) to obtain the compound having the formula (XIX): 
wherein n is the same as defined above, and then removing the benzyl group by a catalytic reduction.
In the production method of a compound having the formula (V), a production method of, for example, a compound having the formula (Vh): 
wherein n is the same as defined above, i.e., R1 and Q are halogen atoms, for example, chlorine atoms, and R2 is an 8-chloro group in the formula (V), is comprised of following the method described in the above reference of A. Cattaneo et al. or similar methods to obtain the compound having the formula (XX): 
and following the same procedure as for synthesizing the compound having the above formula (Vc).
In the production method of the compound having the formula (V), a compound where, for example, R1 is a nitrile group, R2 is a hydrogen atom, and Q is a chlorine atom, that is, a compound having the formula (Vi): 
wherein n is the same as.defined above, may comprise reacting trimethylsilyl nitrile to a compound having the above formula (XIII), if necessary, in the presence of zinc iodide or reacting trimethylsilyl nitrile to a compound having the above formula (Vc) in the presence of a palladium catalyst.
In the production method of the compound having the formula (V), a production method of, for example, a compound having the formula (Vj): 
where n is the same as defined above, i.e., R1 is an ester group, for example, an ethyl ester, R2 is a hydrogen groups and Q is a chlorine group in the formula (V), is comprised of reacting ethanol to a compound having the above formula (Vi) in the presence of an acid catalyst.
1) Synthesis of Final Compound Having Formula (III)
The production method of the compound having the formula-(III) may be comprised of condensation reacting the benzoxazepine derivative having the formula (V) and an intermediate compound having the formula (XXI): 
wherein R3, R4 and the dotted line are the same as defined above, by an ordinary method.
Here, the intermediate having the formula (V) may be synthesized by the same procedure as the synthesis of the compounds having the general formulas (Va) to (Vj) shown above, for example.
Further, the production method of a pyridine derivative (XXIa): 
where, in general formula (XXI), R3 and R4 are hydrogen atoms and the dotted line indicates the presence of a bond may be comprised of following the method described in reference of H. Fischer et al. (J. Heterocyclic. Chem., vol. 17, p. 333, 1980) or similar methods to convert the known compound 2,4xe2x80x2-dipyridyl to a compound having the formula (XXII): 
wherein R5 is a C1-C4 lower alkyl group, benzyl group, or methoxybenzyl group and X is a halogen atom, then reducing it with sodium borohydride to obtain a compound having the formula (XXVIIIa): 
wherein R5 is the same as defined above, then reacting the compound with ethyl chloroformate, phenyl chloroformate, 1-chloroethyl chloroformate, or 2-trimethylsilylethyl chloroformate etc. to obtain a compound of the general formula (XXIVa): 
wherein R6 is a C1-C4 lower alkyl group, 1-chloroethyl group, phenyl group, or 2-trimethylsilylethyl group.
The compound thus obtained is then decomposed with an alcohol such as methanol, ethanol, or hydrolyzed with an acid such as hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, or decomposed with a fluoride such as tetrabutylammonium fluoride (TBAF) so as to obtain the useful synthetic intermediate pyridine derivative having the formula (XXIa).
Further, for example, the pyridine derivative (XXIb) 
where, in the general formula (XXI), for example, R3 and R4 are hydrogen atoms and the dotted line indicates the absence of a bond can be obtained by hydrogenattas the compound having the formula (XXIIIa) in the presence of a palladium/carbon catalyst and, optionally, by adding an acid-such as hydrochloric acid to obtain the compound having the formula (XXIIIb): 
wherein R5 is the same as defined above, then reacting the compound with ethyl chloroformate, phenyl chloroformate, 1-chloroethyl chloroformate, 2-trimethylsilylethyl chloroformate, etc. to obtain the compound having the formula (XXIVb): 
wherein R6 is a C1-C4 lower alkyl group, 1-chloroethyl group, phenyl group, or 2-trimethylsilylethyl group.
The obtained compound (XXIVb) is then decomposed with an alcohol such as methanol, ethanol, or hydrolyzed with an acid such as hydrochloric acid, acetic acid, sulfuric acid, bromic acid, or decomposed with a fluoride such as tetrabutylammonium fluoride (TBAF) so as to obtain the useful synthetic intermediate pyridine derivative (XXIb).
The piperidylpyridine (XXIb) can be obtained by direct catalytic reduction of 1,2,3,6-tetrahydropyridyl pyridine having the formula (XXIa).
The production method of the final compound (III) comprises replacement condensation of a synthetic intermediate having the formula (XXI), for example, a synthetic intermediate pyridine derivative such as illustrated in the above (XXIa to XXIb), with the synthetic intermediate (V) such as illustrated in the above (Va to Vj) and optionally, using a catalyst such as a base (e.g., triethylamine or potassium carbonate) or sodium iodide.
2) Synthesis of Final Compound Having Formula (III) by Separate Method
The production method of the final compound (III) may be comprised of synthesis through the synthetic intermediate having the formula (VI): 
where R1, R2, R3, R4, X, and n are the same as defined above.
Here, the production method of the synthetic intermediate having the formula (VI) may be carried out as follows: That is, a production method of a useful synthetic intermediate having the above formula (VI) by reacting a 2,4xe2x80x2-dipyridyl derivative having the above formula (II) to the compound having the formula (Vk), which corresponds to the compound having the above formula (V), where, for example, Q is a chlorine atom; 
wherein R1, R2, and n are the same as defined above in the presence of sodium iodide.
It may also be comprised as a method of production of a final compound (III) by reacting sodium borohydride to the synthetic intermediate (VI) obtained.
Examples 19 to 27 show the production methods of the above benzoxazepine derivatives and the salts thereof.